BS42023 L3+4

Question 1

what are the primary symptoms of PD? (4)

Answer 1

• Muscle rigidity or stiffness
• Resting rhythmic tremor
• Bradykinesia (slowing of physical movement)
• Postural instability/abnormality

Question 2

what are the secondary symptoms of PD? (7)

Answer 2

• depression
• dementia/confusion
• speech and swallowing difficulties
• drooling
• dizziness
• impotence
• urinary frequency and constipation.

Question 3

what structures make up the basal ganglia? (5)

Answer 3

1. Caudate
2. Putamen
3. Globus pallidus (internal and external segments)
4. Subthalamic nucleus
5. Substantia nigra (pars compacta and reticulata)

Question 4

what is the key function of the basal ganglia?

Answer 4

the initiation and direction of voluntary movement

Question 5

what is the simplified circuitry of the basal ganglia?

Answer 5

cortex –> striatum (caudate then putamen) –> globus pallidus (internal segment) –> thalamus –> cortex

Question 6

what are the neuropathological hallmarks of PD? (2)

Answer 6

1. Loss of nigrostriatal DA neurons

2. presence of Lewy bodies.

Question 7

where are the cell bodies of the nigrostriatal DA neurons?

Answer 7

in the substantia nigra pars compacta (project to the putamen)

Question 8

why does SNpc depigmentation occur in PD?

Answer 8

due to the loss of SNpc DA neurons which have neuromelanin in them

Question 9

on the onset of PD what proportion of putamen and SNpc DA neurons have depleted?

Answer 9

80% Putamen, 60% SNpc

Question 10

what are other neurochemical changes that occur in PD?

Answer 10

Neurodegeneration and LB formation occurs in;

• noradrenergic neurons of the Locus coeruleus
• serotonergic neurons in the Raphe nucleus
• cholinergic neurons in the dorsal motor nucleus of the vagus.

Question 11

what are Lewy bodies?

Answer 11

intraneuronal proteinaceous cytoplasmic inclusions

Question 12

what is a major component of Lewy bodies?

Answer 12

fibrillar a-synuclein

Question 13

what do a-synuclein knockout mice indicate?

Answer 13

a-synuclein is involved in synaptic vesicle recycling and DA neurotransmission

Question 14

what does mutant a-synuclein result in? (3)

Answer 14

• intraneuronal inclusions
• mitochondrial DNA damage
• apoptosis of neocortical, brainstem and motor neurons

Question 15

what does Parkin do?

Answer 15

it is an important enzyme that tags target proteins with ubiquitin for degradation.

Question 16

what is UCH-L1 involved in?

Answer 16

catalysis hydrolysis of C-terminal ubiquityl esters and involved in recycling ubiquitin ligated to misfolded proteins.

Question 17

what does DJ-1 do?

Answer 17

. DJ-1 is thought to be a cellular monitor of oxidative stress

Question 18

describe the ubiquitin-proteasome system (5)

Answer 18

• Ubiquitin monomers (Ub) are activated by E1 and transferred to Ub-conjugating enzyme (E2).
• Proteins are recognised by E3 ligase (parkin) which transfers to Ub to target protein.
• Ub monomers are attached to lysine residue (K) causing poly Ub chain formation.
• Poly Ub chains are linked by K29/K48 target proteins for degradation- producing small peptide fragments.
• Poly Ub chains are recycled to free monomers by enzymes like UCH-L1 for subsequent rounds of ubiquitination.

Question 19

what does mutant LRRK2 do?

Answer 19

mutant LRRK2 interferes with cytoskeletal motility and vesicular trafficking events

Question 20

what are the two main hypotheses of mechanisms of PD?

Answer 20

• Misfolding and aggregation of proteins are instrumental in death of SNpc DA neurons.
• Mitochondrial dysfunction and consequent oxidative stress, lead to cell death.

Question 21

what is the evidence for misfolding and aggregation of proteins?

Answer 21

Abnormal deposits of protein in brain tissue is a feature of several neurodegenerative disorders including PD. Although composition and localisation of protein aggregates differs from disease to disease, aggregation of proteins is a common feature.

Question 22

what is the evidence for mitochondrial dysfunction and oxidative stress?

Answer 22

Defects in oxidative phosphorylation in PD suggested as MPTP blocks mitochondrial electron transport chain by inhibiting complex I (NADH dehydrogenase). Abnormalities in mitochondrial complex I have also been identified in PD.

Question 23

what are the effects of complex I inhibition?

Answer 23

Inhibition of complex I increases ROS superoxide. This forms toxic hydroxyl radicals or reacts with NO to form peroxinitrite. These cause cellular damage by reacting with nucleic acids, proteins and lipids.

Question 24

what is the evidence for programmed cell death in PD?

Answer 24

There is an increase in the number of Bax-positive SNpc DA neurons in PD. Other molecular markers of PCD are also altered in PD including caspase-8, caspase-9 and Bcl-xL. (post-mortem tissues)

Question 25

what are the main animal models of PD?

Answer 25

``` Toxin-based models: - 6-OHDA - Paraquat - Rotenone - MPTP Gene-based models: - Synuclein - Parkin - LRRK2 - DJ-1 ```

Question 26

what are the pros and cons of the 6-OHDA model?

Answer 26

Pros: Good model for assessing anti-PD actions of new drugs as unilateral striatal lesion causes quantifiable (related to degree of lesion/how many cells have died) asymmetric circling behaviour in animals. (administer to just one hemisphere of brain). Cons: Not clear if the mechanism of cell death is similar to human PD. 6-OHDA-induced pathology different from PD (formation of Lewy bodies-can’t look at Lewy body contribution to disease). Pathology also varies depending on injection site of 6-OHDA. Need to know exactly where you are injecting your toxin so you can compare with other studies in the field.

Question 27

what are the pros and cons of the MPTP model?

Answer 27

pros: Low dose MPTP treated monkeys show preferential degeneration of putamen vs caudal DA nerve terminals, replicates what you see in humans. The regional pattern of MPTP-induced damage is similar to human PD (there is more cell loss in SNpc than in VTA. DA neuromelanin-containing cells are more susceptible to damage). cons: Other monoaminergic neurons (e.g. in locus coeruleus) are not damaged by MPTP. Similar to 6-OHDA model, classical Lewy bodies are not found in MPTP-intoxicated humans/monkeys.

Question 28

what are the pros and cons of the rotenone model?

Answer 28

Pros: May be a good model for studying the relationship between aggregate formation and cell death. Cons: Rotenone has widespread neurotoxic actions- it is not DA selective although these are the main target for its action within the brain.

Question 29

what are the pros and cons of the paraquat model?

Answer 29

Pros: This model may be a useful model to study the role of a-synuclein in neuro-degeneration as it reliably causes DA cell loss and a-synuclein positive inclusions). Cons: It is not known if DA toxicity is selective or if other neurons are affected.